Loss of OVOL2 in Triple-Negative Breast Cancer Promotes Fatty Acid Oxidation Fueling Stemness Characteristics.

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.

Methyl gallate: Review of pharmacological activity.

Methyl gallate (MG) is a polyphenolic compound widely found in natural plants. MG has been shown to have a variety of biological functions, including anti-tumor, anti-inflammatory, anti-oxidant, neuroprotective, hepatoprotective and anti-microbial activities, and has broad research and development prospects. A total of 88 articles related to MG were searched using the PubMed, Science Direct, and Google Scholar databases, systematically investigating the pharmacological activity and molecular mechanisms of MG. There were no restrictions on the publication years, and the last search was conducted on June 5, 2023. MG can exert pharmacological effects through multiple pathways and targets, such as PI3K/Akt, ERK1/2, Caspase, AMPK/NF-κB, Wnt/ß-catenin, TLR4/NF-κB, MAPK, p53, NLRP3, ROS, EMT. According to the literature, MG has the potential to be a prospective adjuvant for anticancer therapy and deserves further study.

RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling.

Breast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.

Prognostic Significance of ANGPTL4 in Lung Adenocarcinoma: A Meta-Analysis Based on Integrated TCGA and GEO Databases.

Lung adenocarcinoma (LUAD) is a common malignant tumor with a poor prognosis. Recent studies have found that angiopoietin-like 4 (ANGPTL4) is abnormally expressed in many tumors, so it can serve as a potential prognostic marker and therapeutic target. However, its prognostic value in LUAD remains unclear. We downloaded RNA sequence data for LUAD from The Cancer Genome Atlas (TCGA) database, methylation data from the University of California Santa Cruz genome database, and clinical information. R software (version 4.1.1) was applied to analyze the ANGPTL4 expression in LUAD and nontumor samples, and the correlation with clinical characteristics to assess its prognostic and diagnostic value. In addition, we analyzed the relationship between the ANGPTL4 expression and methylation levels. Tumor IMmune Estimation Resource (TIMER) tool was taken for immune infiltration analysis, and two Gene Expression Omnibus (GEO) datasets were combined for meta-analysis. Finally, differentially expressed genes (DEGs) related to ANGPTL4 were analyzed to clarify its function. As shown in our results, ANGPTL4 was upregulated in LUAD and was an independent risk factor for the diagnosis and prognosis of LUAD. The general methylation level and eight ANGPTL4 methylation sites were significantly negatively correlated with the ANGPTL4 expression. Furthermore, we found that B cell infiltration was negatively correlated with ANGPTL4 expression and was an independent risk factor. Meta-analysis showed that the high expression of ANGPTL4 was closely associated with a poor prognosis. 153 DEGs, including the matrix metalloproteinase family, the chemokines subfamily, and the collagen family, were correlated with ANGPTL4. In this study, we found that ANGPTL4 was significantly elevated in LUAD and was closely associated with the development and poor prognosis of LUAD, suggesting that ANGPTL4 may be a prognostic biomarker and a potential therapeutic target for LUAD.

Methyl Gallate Suppresses the Migration, Invasion, and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma Cells via the AMPK/NF-κB Signaling Pathway in vitro and in vivo.

Methyl gallate (MG), a polyphenolic compound found in plants, is widely used in traditional Chinese medicine. MG is known to alleviate several cancer symptoms. However, most studies that have reported the antitumor effects of MG have done so at the cellular level, and the inhibitory effect and therapeutic mechanism of MG in hepatocellular carcinoma (HCC) have not been extensively explored in vivo. We aimed to understand the therapeutic mechanism of MG in HCC in vitro and in vivo. MTT and colony formation assays were used to determine the impact of MG on the proliferation of a human HCC cell line, BEL-7402; wound healing and transwell assays were used to quantify the migration and invasion of HCC cells. Western blotting was used to quantify the expression of the AMPK/NF-κB signaling pathway proteins. In vivo tumor growth was measured in a xenograft tumor nude mouse model treated with MG, and hematoxylin-eosin staining and immunohistochemistry (IHC) were used to visualize the histological changes in the tumor tissue. We found that MG showed anti-proliferative effects both in vitro and in vivo. MG downregulated the protein expression of AMPK, NF-κB, p-NF-κB, and vimentin and upregulated the expression of E-cadherin in a dose-dependent manner. Additionally, MG inhibited the migration and invasion of HCC cells by decreasing MMP9 and MMP2 expression and increasing TIMP-2 expression. These were consistent with the results of IHC in vivo. MG inhibited the proliferation, migration, and invasion of HCC cells. This effect potentially involves the regulation of the AMPK/NF-κB pathway, which in turn impacts epithelial-mesenchymal transition and MMP expression.

TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. More than 70% of breast cancers are estrogen receptor (ER) alpha positive. Compared with ER alpha-negative breast cancer, which is more aggressive and has a shorter survival time, ER alpha-positive breast cancer could benefit from endocrine therapy. Selective estrogen receptor modulators, such as tamoxifen, are widely used in endocrine therapy. Approximately half of ER alpha-positive breast cancer patients will eventually develop endocrine resistance, making it a major clinical challenge in therapy. Thus, decoding the throughput of estrogen signaling, including the control of ER alpha expression and stability, is critical for the improvement of breast cancer therapeutics. METHODS: TRIM3 and ER alpha protein expression levels were measured by western blotting, while the mRNA levels of ER alpha target genes were measured by RT-PCR. A CCK-8 assay was used to measure cell viability. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling activity was accomplished with luciferase assays, RT-PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect ER alpha protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the ER alpha protein. RESULTS: In our current study, we found that TRIM3, an E3 ligase, can promote ER alpha signaling activity and breast cancer progression. TRIM3 depletion inhibits breast cancer cell proliferation and migration, while unbiased RNA sequencing data indicated that TRIM3 is required for the activity of estrogen signaling on the -genome-wide scale. The immunoprecipitation assays indicated that TRIM3 associates with ER alpha and promotes its stability, possibly by inducing K63-linked polyubiquitination of ER alpha. In conclusion, our data implicate a nongenomic mechanism by which TRIM3 stabilizes the ER alpha protein to control ER alpha target gene expression linked to breast cancer progression. CONCLUSION: Our study provides a novel posttranslational mechanism in estrogen signaling. Modulation of TRIM3 expression or function could be an interesting approach for breast cancer treatment. Video abstract.

Meta-analysis on the safety and efficacy of early oral feeding after total laryngectomy.

PURPOSE: To evaluate the safety and efficacy of early oral feeding (≤ 3 days) and delayed oral feeding (≥ 7 days) following total laryngectomy. METHODS: Relevant literatures on early and delayed oral feeding following total laryngectomy published before January, 2019 were searched in PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and Wanfang Database. Two reviewers were responsible for selecting literatures, extracting data and cross-check. The incidence of pharyngocutaneous fistula (PCF) was evaluated by calculating OR and 95%CI. Difference in length of stay (LOS) of patients undergoing early oral feeding or delayed oral feeding was compared using standardized mean difference (SMD) and 95%CI. Sensitivity analysis and publication bias examination were conducted. RESULTS: 14 eligible literatures were enrolled, including 1824 patients who underwent total laryngectomy, with 1250 cases of early oral feeding and 574 cases of delayed oral feeding. The incidence of PCF was similar in patients receiving early oral feeding or delayed oral feeding following total laryngectomy (OR=1.12, 95%CI=0.81-1.54). LOS was shorter in cases of early oral feeding than those of delayed oral feeding (SMD=-0.77, 95%CI=-1.18-0.36). Reliable conclusions were obtained without obvious publication bias. CONCLUSIONS: Early oral feeding following total laryngectomy shortens LOS relative to delayed oral feeding. No significant difference in the incidence of PCF is observed between early oral feeding and delayed oral feeding, suggesting that early oral feeding following total laryngectomy is safe and efficacious.

The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability.

Chemotherapy is widely used in a variety of solid tumors, such as lung cancer, gastric cancer and breast cancer. The genotoxic drugs, such as cisplatin, suppress cancer progression either by inhibition cell proliferation or facilitating apoptosis. However, the chemotherapy resistance remains an urgent challenge in cancer therapy, especially in advanced stages. Several studies showed that the activation of pro-survival pathways, such as PI3K-AKT, participated in mediating chemotherapy resistance. The insights into the molecular mechanisms for underlying chemotherapy resistance are of great importance to improve cancer patient survival in advanced stages. The HOIP protein belongs to the RING family E3 ubiquitin ligases and modulates several atypical ubiquitination processes in cellular signaling. Previous studies showed that HOIP might be an important effector in modulating cancer cell death under genotoxic drugs. Here, we report that HOIP associates with PTEN and facilitates PTEN degradation in cancer cells. Depletion of HOIP causes cell cycle arrest and apoptosis, which effects could be rescued by PTEN silencing. Besides, the survival data from public available database show that HOIP expression correlates with poor survival in several types of chemotherapy-treated cancer patients. In conclusion, our study establishes a novel mechanism by which HOIP modulates PTEN stability and facilitates chemotherapy resistance in malignancies.

ZNF213 Facilitates ER Alpha Signaling in Breast Cancer Cells.

BACKGROUND: Breast cancer is the most common women malignancy worldwide, while estrogen receptor alpha positive type accounts for two third of all breast cancers. Although ER alpha positive breast cancer could be effectively controlled by endocrine therapy, more than half of the cases could develop endocrine resistance, making it an important clinical issue in breast cancer treatment. Thus, decoding the detailed mechanism, which controls ER alpha signaling activation and ER alpha protein stability, is of great importance for the improvement of breast cancer therapy. Several zinc finger proteins were shown to mediate the ubiquitination process and modulate protein stability. Thus, we further explore the function of Zinc finger protein 213 on ER alpha protein stability and tamoxifen resistance. METHODS: CCK8 and Edu assay was used to measure cell proliferation. RNA sequence was performed by Ingenuity pathway analysis. The ER alpha signaling activities were measured with luciferase assay, real-time quantitative PCR, and western blotting. Protein stability assay and ubiquitin assay were used to determine ER alpha protein degradation and ubiquitination. The immuno-precipitation was utilized to determine ER alpha and ZNF213 interaction. The ubiquitin-based immuno-precipitation assay was sued to detect specific ubiquitination manner on ER alpha. RESULTS: We identified ZNF213 as a novel zinc finger protein, which modulated ER alpha protein. ZNF213 expression correlated with poor outcome in endocrine treated patients. ZNF213 depletion inhibited ER alpha signaling and proliferation in breast cancer cells. Further mechanistic studies showed ZNF213 located in cytosol and nuclear, which modulated ER alpha stability via inhibiting ER alpha K48-linked ubiquitination. CONCLUSIONS: Our study reveals an interesting post-translational mechanism between ER alpha and ZNF213 in breast cancer. Targeting ZNF213 could be an appealing strategy for ER alpha positive breast cancer.

The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression.

Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.

Estrogen receptor regulates immune defense by suppressing NF-κB signaling in the Crassostrea hongkongensis.

The crosstalk between the estrogen receptor (ER) and NF-κB signalling pathways has merged in vertebrates and plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. However, such crosstalk between the endocrine and immune systems needs to be explored in lower invertebrates. In this study, we identified a 2856-bp homologue of the estrogen receptor from Hong Kong oyster (ChER), containing a 5' untranslated region (UTR) of 234 bp, a 3' UTR of 387 bp, and an open reading frame (ORF) of 2235 bp. We observed that overexpression of ChER suppressed ChRel-dependent NF-kappaB (NF-κB) activation in the HEK293T (human embryonic kidney 293T) cell line, and depletion of ChER in vivo resulted in upregulation of two NF-κB-responsive marker genes, namely, TNF-α and IL-17, which confirmed its potential role in controlling NF-κB signalling. Furthermore, an EMSA (electrophoretic mobility shift assay) showed that ChER could negatively regulate the binding of ChRel to NF-κB probe-responsive elements. Serial domain requirement analysis showed that both region C (DNA-binding domain) and region E (ligand-binding domain) of ChER were essential for mediating the crosstalk underlying ChER-dependent NF-κB suppression. In conclusion, we demonstrate for the first time the negative regulatory role of the ER in NF-κB signalling in oysters, strongly indicating the presence of complex crosstalk between the endocrine and immune systems in lower marine molluscs.

DNA Methylation: A Potential Biomarker of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a serious public health concern worldwide. By 2040, 4.41 million people are estimated to expire annually due to COPD. However, till date, it has remained difficult to alter the activity or progress of the disease through treatment. In order to address this issue, the best way would be to find biomarkers and new therapeutic targets for COPD. DNA methylation (DNAm) may be a potential biomarker for disease prevention, diagnosis, and prognosis, and its reversibility further makes it a potential drug design target in COPD. In this review, we aimed to explore the role of DNAm as biomarkers and disease mediators in different tissue samples from patients with COPD.

Xiaoqinglong Decoction Protects the Lungs of AECOPD Mice through the AMPK/mTOR Signaling Pathway.

METHOD: Male C57BL/6J mice were used to establish AECOPD model by cigarette smoke and bacterial exposure. Mice were randomly divided into normal control (NC), AECOPD, XQLD, Compound C (Com C), Com C + XQLD, and Clarithromycin (CLA) groups. After treatment, the pulmonary function was evaluated by whole-body plethysmograph. The lung histopathology was observed by HE staining. The serum levels of IL-6, TNF-α, and COX-2 were detected by ELISA assay. The apoptotic index was measured by TUNEL assay, and the protein expressions of Bax, Bcl-2, Caspase-3, GRP78, and CHOP in the lung tissues were measured by western blot assay. RESULTS: XQLD treatment can improve pulmonary function (PF), ameliorate lung injury, and suppress inflammation and apoptosis of lung tissues. In addition, XQLD also markedly attenuated endoplasmic reticulum stress (ERS) and activated AMPK/mTOR pathway in the lung tissues of mice with AECOPD. However, the AMPK inhibitor Compound C decreased the protective effect of XQLD in AECOPD mice. CONCLUSION: These findings suggested that XQLD has protective effect against inflammation and apoptosis in AECOPD mice by attenuating ER stress via AMPK/mTOR pathway.

Regulatory innate lymphoid cells suppress innate immunity and reduce renal ischemia/reperfusion injury.

Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal inflammation. However, the expression and role of regulatory innate lymphoid cells in kidney has not been reported. Here, we show that regulatory innate lymphoid cells are present in both human and mouse kidney, express similar surface markers and form a similar proportion of total kidney innate lymphoid cells. Regulatory innate lymphoid cells from kidney were expanded in vitro with a combination of IL-2, IL-7 and transforming growth factor-ß. These cells exhibited immunosuppressive effects on innate immune cells via secretion of IL-10 and transforming growth factor-ß. Moreover, treatment with IL-2/IL-2 antibody complexes (IL-2C) promoted expansion of regulatory innate lymphoid cells in vivo, and prevent renal ischemia/reperfusion injury in Rag-/- mice that lack adaptive immune cells including Tregs. Depletion of regulatory innate lymphoid cells with anti-CD25 antibody abolished the beneficial effects of IL-2C in the Rag-/- mice. Adoptive transfer of ex vivo expanded regulatory innate lymphoid cells improved renal function and attenuated histologic damage when given before or after induction of ischemia/reperfusion injury in association with reduction of neutrophil infiltration and induction of reparative M2 macrophages in kidney. Thus, our study shows that regulatory innate lymphoid cells suppress innate renal inflammation and ischemia/reperfusion injury.

Neuroendocrine immune-regulatory of a neuropeptide ChGnRH from the Hongkong oyster, Crassostrea Hongkongensis.

It is increasingly appreciated that neuroendocrine-immune interactions hold the key to understand the complex immune system. In this study, we explored the role of a reproductive regulation-related hormone, GnRH, in the regulation of immunity in Hong Kong oysters. We found that vibrio bacterial strains injection increased the expression of ChGnRH. Moreover, ChGnRH neuropeptide promotes the phagocytic ability and bacterial clearance effect of hemocytes which regarded to be the central immune organ. The content of cAMP after incubation with ChGnRH peptide was increased, which could be blocked by adenylyl cyclase inhibitor SQ 22,536. Furthermore, the stimulated effect of ChGnRH peptide on the phagocytosis and bacterial clearance was also blocked by SQ 22,536, H89 and enzastaurin, strongly demonstrating that cAMP dependent PKA and PKC signaling pathway was involved in ChGnRH mediated immune regulation. In conclusion, this study confirms the presence of neuroendocrine-immune regulatory system in marine invertebrates, which contributes to understand the complexity of oyster immune defense system.

Chloride channel-3 mediates multidrug resistance of cancer by upregulating P-glycoprotein expression.

Chloride channel-3 (ClC-3), a member of the ClC family of voltage-gated Cl- channels, is involved in the resistance of tumor cells to chemotherapeutic drugs. Here, we report a new mechanism for ClC-3 in mediating multidrug resistance (MDR). ClC-3 was highly expressed in the P-glycoprotein (P-gp)-dependent human lung adenocarcinoma cell line (A549)/paclitaxel (PTX) and the human breast carcinoma cell line (MCF-7)/doxorubicin (DOX) resistant cells. Changes in the ClC-3 expression resulted in the development of drug resistance in formerly drug-sensitive A549 or MCF-7 cells, and drug sensitivity in formerly drug-resistant A549/Taxol and MCF-7/DOX cells. Double transgenic MMTV-PyMT/CLCN3 mice with spontaneous mammary cancer and ClC-3 overexpression demonstrated drug resistance to PTX and DOX. ClC-3 expression upregulated the expression of MDR1 messenger RNA and P-gp by activating the nuclear factor-κB (NF-κB)-signaling pathway. These data suggest that ClC-3 expression in cancer cells induces MDR by upregulating NF-κB-signaling-dependent P-gp expression involving another new mechanism for ClC-3 in the development of drug resistance of cancers.

Identification and functional characterization of NEMO in Crassostrea gigas reveals its crucial role in the NF-κB activation.

NEMO (NF-κB essential modulator) is one of the important regulatory subunits of the IκB kinase (IκK) complex that controls the activation of the NF-κB signaling pathway. Here, we have identified the homolog of NEMO from the pacific oyster Crassostrea gigas. CgNEMO harbors the conserved the IκK binding region, NEMO ubiquitin binding domain and Zinc finger domain. In terms of tissue distribution, CgNEMO is expressed in various tissues with an observed highest expression in the hemocytes. Furthermore, infection by two related Vibrio strains significantly increased CgNEMO expression in the hemocytes. Cell culture based luciferase reporter assays showed that CgNEMO activates the NF-κB reporter in a dose-pendent manner. Moreover, CgNEMO was also found to counter the IkB-dependent inhibitory effect on NF-κB activation, providing a plausible mechanism of NF-κB activation by CgNEMO. Meanwhile, site-directed mutagenesis demonstrated that the putative ubiquitination site K535 is required for the activation of NF-κB, implying that ubiquitination of NEMO may be involved in regulating its activity. Finally, RNAi mediated knockdown of CgNEMO in vivo significantly compromised the bacterial induction of key cytokines TNF-α and IL-17, strongly suggesting a role for CgNEMO in acute immune defense in oyster. In conclusion, this study provides new insights into our understanding about the evolution of NEMO mediated NF-κB activation and the induction of cytokine. Our findings may provide valuable information about diseases control and management in oyster aquaculture.

Potentiating Tissue-Resident Type 2 Innate Lymphoid Cells by IL-33 to Prevent Renal Ischemia-Reperfusion Injury.

The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33-treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo-expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of amphiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo-expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33-ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy.

HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

IL-25 Elicits Innate Lymphoid Cells and Multipotent Progenitor Type 2 Cells That Reduce Renal Ischemic/Reperfusion Injury.

IL-25 is an important immune regulator that can promote Th2 immune response-dependent immunity, inflammation, and tissue repair in asthma, intestinal infection, and autoimmune diseases. In this study, we examined the effects of IL-25 in renal ischemic/reperfusion injury (IRI). Treating IRI mice with IL-25 significantly improved renal function and reduced renal injury. Furthermore, IL-25 treatment increased the levels of IL-4, IL-5, and IL-13 in serum and kidney and promoted induction of alternatively activated (M2) macrophages in kidney. Notably, IL-25 treatment also increased the frequency of type 2 innate lymphoid cells (ILC2s) and multipotent progenitor type 2 (MPP(type2)) cells in kidney. IL-25-responsive ILC2 and MPP(type2) cells produced greater amounts of Th2 cytokines that associated with the induction of M2 macrophages and suppression of classically activated (M1) macrophages in vitro. Finally, adoptive transfer of ILC2s or MPP(type2) cells not only reduced renal functional and histologic injury in IRI mice but also induced M2 macrophages in kidney. In conclusion, our data identify a mechanism whereby IL-25-elicited ILC2 and MPP(type2) cells regulate macrophage phenotype in kidney and prevent renal IRI.